Major depressive disorder (MDD) is a serious, debilitating illness that affects 16.6% of the US population in their lifetime. One of the most critical issues in developing new treatments is that in double-blind clinical trials the administration of placebo in MDD can often mimic the effects of FDA-approved antidepressants and lead to a significant improvement in approximately 35% of patients. At present the neurobiological mechanisms underlying placebo responses in MDD are unknown. We hypothesize that mesolimbic dopaminergic pathways implicated in reward anticipation, reinforcement learning, and expectation play a critical role in mediating placebo responses in MDD. In this research we will use integrated PET/fMRI imaging techniques, to compare simultaneously [11C]raclopride displacement (an indirect measure of endogenous dopamine release) and BOLD signals within the mesolimbic pathways in patients with MDD who are responders versus non-responders to placebo. The proposed research is profoundly innovative with respect to trial design, technology, and its multi-level integration, probing psychological an neurobiological constructs assumed to be crucially implicated in placebo response. A better understanding of the neurobiological basis of placebo effect has enormous potential for harnessing the healing capacity of placebo, developing new generations of clinical trials yielding better differentiation between novel antidepressants and placebo, and ultimately leading to new treatments for MDD.